Project Abstract One of the major goals of the BRAIN initiative is to develop technologies capable of interfacing with specific neural circuits in the human brain. Ultrasonic neuromodulation (UNM) is among the most significant new technologies being developed for this purpose because it has the potential to non-invasively modulate neural activity in deep-brain regions with millimeter spatial precision. This unique capability would complement existing neuromodulation and imaging techniques in basic and clinical applications. However, despite a surge of interest in UNM, the lack of knowledge about its mechanisms and recent findings of off-target sensory effects accompanying direct neuromodulation pose significant challenges to the use of this technology in human neuroscience. In particular, while most groups working on UNM are racing ahead with device development and applications, we have uncovered a major issue with this technology that must be addressed before it can be used reliably by the neuroscience community: at the ultrasonic parameters used in most UNM studies, ultrasound causes not only direct neuromodulation of the targeted region, but also strong activation of auditory cortical circuits. This significantly confounds the interpretation of UNM-evoked electrical and motor responses seen in animal models, our understanding of efficacious doses and parameters, and most importantly, potential applications in humans. To overcome this issue, we will (1) establish an understanding of the mechanisms and parameters of both direct and indirect effects of ultrasound on neural circuits, (2) identify parameters for maximizing direct modulation, and (3) develop sham stimuli enabling properly controlled use of UNM as a tool for human neuroscience. To tackle these problems, we have assembled a multidisciplinary team of scientists and engineers with expertise in tissue mechanics, acoustics, biophysics, systems neuroscience, and human psychophysics who will use unique experimental approaches ranging from computational models to specially-developed transgenic rodents and human volunteers. If successful, this project will help resolve a key issue preventing focused ultrasound from serving as a reliable, interpretable modality for non-invasive neuromodulation, and lay the groundwork for the development of optimized devices and appropriate controls for widespread use of UNM in the study of brain circuits.